US8324389B2 - Solid forms of a Raf kinase inhibitor - Google Patents

Solid forms of a Raf kinase inhibitor Download PDF

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US8324389B2
US8324389B2 US12/529,258 US52925808A US8324389B2 US 8324389 B2 US8324389 B2 US 8324389B2 US 52925808 A US52925808 A US 52925808A US 8324389 B2 US8324389 B2 US 8324389B2
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imidazol
trifluoromethyl
methyl
inhibitors
tga
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US20100209418A1 (en
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Ahmad Hashash
Kangwen L. Lin
Augustus O. Okhamafe
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

  • the present invention is directed to solid forms of the Raf kinase inhibitor 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, as well as compositions thereof and uses of the same.
  • kinases known to be associated with tumorigenesis include the Raf serine/threonine kinases and the receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • Raf serine/threonine kinases are essential components of the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling module that controls a complex transcriptional program in response to external cellular stimuli.
  • Raf genes code for highly conserved serine-threonine-specific protein kinases which are known to bind to the ras oncogene. They are part of a signal transduction pathway believed to consist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1 (ERK activator or MAPKK) kinases and ERK (MAPK) kinases, which ultimately phosphorylate transcription factors.
  • Raf kinases are activated by Ras and phosphorylate and activate two isoforms of Mitogen-Activated Protein Kinase Kinase (called Mek1 and Mek2), that are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 or Erk1 and Erk2).
  • MEPK Mitogen Activated Kinases 1 and 2
  • the MAPKs phosphorylate many substrates including transcription factors and in so doing set up their transcriptional program.
  • Raf kinase participation in the Ras/MAPK pathway influences and regulates many cellular functions such as proliferation, differentiation, survival, oncogenic transformation and apoptosis.
  • Raf-1 phosphorylates and activates Mek1, resulting in the propagation of the signal to downstream effectors, such as MAPK (mitogen-activated protein kinase; Crews et al., 1993, Cell 74:215).
  • MAPK mitogen-activated protein kinase
  • the Raf serine/threonine kinases are considered to be the primary Ras effectors involved in the proliferation of animal cells (Avruch et al., 1994, Trends Biochem. Sci. 19:279).
  • Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf, distinguished by their ability to interact with Ras, to activate MAPK kinase pathway, tissue distribution and sub-cellular localization (Marias et al., Biochem. J. 351:289-305, 2000; Weber et al., Oncogene 19:169-176, 2000; Pritchard et al., Mol. Cell. Biol. 15:6430-6442, 1995).
  • Ras/Raf/MEK/ERK pathway Activating mutation of one of the Ras genes can be seen in about 20% of all tumors and the Ras/Raf/MEK/ERK pathway is activated in about 30% of all tumors (Bos et al., Cancer Res. 49:4682-4689, 1989; Hoshino et al., Oncogene 18:813-822, 1999). Recent studies have shown that B-Raf mutation in the skin nevi is a critical step in the initiation of melanocytic neoplasia (Pollock et al., Nature Genetics 25: 1-2, 2002).
  • Melanoma which continues to represent a significant unmet medical need, is a complex multigenic disease with a poor prognosis, especially in the advanced metastatic state. Activating somatic mutations in the B-Raf proto-oncogene have recently been discovered in a variety of malignancies, and most frequently in melanoma. Approximately 70% of melanoma express a mutated and activated form of B-Raf (V600E), making it an excellent target for drug development. Furthermore, another 10-15% of melanomas express mutant N-Ras, further demonstrating the importance of the MAPK pathway in the growth and survival of melanoma cells.
  • Inhibitors of the Ras/Raf/MEK/ERK pathway at the level of Raf kinases can potentially be effective as therapeutic agents against tumors with over-expressed or mutated receptor tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2 (an adapter protein that allows stimulation of Ras by the Sos exchange factor) as well as tumors harboring activating mutations of Raf itself.
  • Grb2 an adapter protein that allows stimulation of Ras by the Sos exchange factor
  • inhibitors of Raf-1 kinase that also inhibit B-Raf have shown promise as therapeutic agents in cancer therapy (Crump, Current Pharmaceutical Design 8:2243-2248, 2002; Sebastien et al., Current Pharmaceutical Design 8: 2249-2253, 2002).
  • Raf kinase inhibitors have been described as exhibiting efficacy in inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Pat. Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391).
  • Other patents and patent applications suggest the use of Raf kinase inhibitors for treating leukemia (see, e.g., U.S. Pat. Nos. 6,268,391, and 6,204,467, and published U.S. Patent Application Nos.
  • Angiogenesis also plays an important role in the growth of cancer cells. It is known that once a nest of cancer cells reaches a certain size, roughly 1 to 2 mm in diameter, the cancer cells must develop a blood supply in order for the tumor to grow larger as diffusion will not be sufficient to supply the cancer cells with enough oxygen and nutrients. Thus, inhibition of angiogenesis is expected to inhibit the growth of cancer cells.
  • Receptor tyrosine kinases are transmembrane polypeptides that regulate developmental cell growth and differentiation, remodeling and regeneration of adult tissues (Mustonen, T. et al., J. Cell Biology 129:895-898, 1995; van der Geer, P. et al., Ann Rev. Cell Biol. 10:251-337, 1994).
  • Polypeptide ligands known as growth factors or cytokines, are known to activate RTKs.
  • Signaling RTKs involves ligand binding and a shift in conformation in the external domain of the receptor resulting in its dimerization (Lymboussaki, A.
  • RTKs Two subfamilies of RTKs are specific to the vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily.
  • Class V RTKs include VEGFR1 (FLT-1), VEGFR2 (KDR (human), Flk-1 (mouse)), and VEGFR3 (FLT-4) (Shibuya, M. et al., Oncogene 5:519-525, 1990; Terman, B. et al., Oncogene 6:1677-1683, 1991; Aprelikova, O. et al., Cancer Res. 52:746-748, 1992).
  • VEGF vascular permeability and endothelial cell proliferation
  • VEGF is known to specifically bind to RTKs including FLT-1 and Flk-1 (DeVries, C. et al., Science 255:989-991, 1992; Quinn, T. et al., Proc. Natl. Acad. Sci. 90:7533-7537, 1993).
  • VEGF stimulates the migration and proliferation of endothelial cells and induces angiogenesis both in vitro and in vivo (Connolly, D. et al., J. Biol. Chem. 264:20017-20024, 1989; Connolly, D. et al., J. Clin. Invest. 84:1470-1478, 1989; Ferrara, N. et al., Endocrinol. Rev. 18:4-25, 1997; Leung, D. et al., Science 246:1306-1309, 1989; Plouet, J. et al., EMBO J. 8:3801-3806, 1989).
  • VEGFR2 mediates the majority of downstream effects of VEGF in angiogenesis (Wey S. et al., Clinical Advances in Hematology and Oncology, 2:37-45, 2004).
  • VEGFR2 mediated proliferation of endothelial cells is believed to involve activation of the Ras/Raf/Mek/Erk pathway (Veikkola T. et al., Cancer Res 60:203-212, 2000).
  • VEGFR2 expression has been observed in melanoma, breast cancer, bladder cancer, lung cancer, thyroid cancer, prostate cancer, and ovarian cancer (see Wey et al., supra).
  • Platelet derived growth factor receptor kinase is another type of RTK.
  • PDGF expression has been shown in a number of different solid tumors, from glioblastomas and osteosarcoma to prostate carcinomas. In these various tumor types, the biological role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and angiogenesis.
  • PDGF interacts with tyrosine kinases receptors PDGFR ⁇ and PDGFR ⁇ . Therefore, inhibiting the PDGFR kinase activity with small molecules is expected to interfere with tumor growth and angiogenesis.
  • the fibroblast growth factor receptor kinases represent another type of RTKs.
  • the fibroblast growth factors are a family of polypeptide growth factors involved in a variety of activities, including mitogenesis, angiogenesis, and wound healing. They comprise a family of related but individually distinct tyrosine kinase receptors containing an extracellular domain with either 2 or 3 immunoglobulin (Ig)-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain.
  • Ig immunoglobulin
  • FGFR1 The fibroblast growth factor receptors that have been identified include FGFR1 (Ruta, M et al, Oncogene 3:9-15, 1988); FGFR2 (Dionne, C et al., Cytogenet. Cell Genet. 60:34-36, 1992); FGFR3 (Keegan, K et al., Proc. Nat. Acad. Sci. 88:1095-1099, 1991); and FGFR4 (Partanen, J et al., EMBO J. 10:1347-1354, 1991).
  • the role of the fibroblast growth factor receptors, particularly FGFR3, in cancer has been illuminated.
  • Dysregulation of oncogenes by translocation to the immunoglobulin heavy chain (IgH) locus on 14q32 is a seminal event in the pathogenesis of B-cell tumors. In multiple myeloma, translocations to the IgH locus occur in 20 to 60% of cases. For most translocations, the partner chromosome is unknown; for the others, a diverse array of chromosomal partners have been identified, with 11q13, the only chromosome that is frequently involved. Bergsagel et al.
  • illegitimate switch recombination fragments (defined as containing sequences from only 1 switch region) as potential markers of translocation events into IgH switch regions in 15 of 21 myeloma cell lines, including 7 of 8 karyotyped lines that had no detectable 14q32 translocation.
  • These translocation breakpoints involved 6 chromosomal loci: 4p16.3; 6; 8q24.13; 11q13.3; 16q23.1; and 21q22.1 (Bergsagel et al., Proc. Nat. Acad. Sci. 93:13931-13936, 1996). Chesi et al. ( Nature Genet.
  • Rasmussen, T et al. cited a frequency of 3 to 24% for the t(4;14) translocation in multiple myeloma (Rasmussen, T et al., Br. J. Haematol. 117:626-628, 2002).
  • the translocation was observed at a significantly lower frequency in patients with monoclonal gammopathy of undetermined significance (MGUS), suggesting a role in the transition from MGUS to multiple myeloma.
  • the t(4;14) translocation affects 2 potential oncogenes: FGFR3 and multiple myeloma set domain (MMSET).
  • Rasmussen et al. investigated the frequency of FGFR3 dysregulation and its prognostic value in multiple myeloma. In 16 of 110 (14.5%) multiple myeloma bone marrow samples, they found dysregulated FGFR3 expression.
  • c-Kit is another receptor tyrosine kinase belonging to PDGF Receptor family and is normally expressed in hematopoietic progenitor, mast and germ cells.
  • C-kit expression has been implicated in a number of cancers including mast cell leukemia, germ cell tumors, small-cell lung carcinoma, gastrointestinal stromal tumors, acute myelogenous leukemia (AML), erythroleukemia, neuroblastoma, melanoma, ovarian carcinoma, breast carcinoma (Heinrich, M. C. et al; J. Clin. Onc. 20, 6 1692-1703, 2002 (review article); Smolich, B. D. et al., Blood, 97, 5; 1413-1421).
  • CSF-1R colony stimulating factor-1
  • CSF-1R colony stimulating factor-1
  • tyrosine kinase receptor which, when activated by its ligand CSF-1, triggers signal transduction pathways controlling cell proliferation and differentiation.
  • CSF-1R is expressed in the mammary gland during pregnancy and lactation. Abnormal CSF-1R expression has been correlated with 58% of all breast cancers, and with 85% of invasive breast carcinoma (see Sapi, supra).
  • the present invention provides solid forms A-P of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine as characterized by, for example, the XRPD, DSC, and TGA data provided herein.
  • the present invention further provides processes of preparing the solid forms described herein, and products resulting from the processes.
  • compositions such as pharmaceutical compositions, that comprise a solid form described herein and at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods for treating cancer in a human or animal subject, comprising administering to the human or animal subject a solid form of the invention, or pharmaceutical composition comprising the same.
  • the present invention further provides methods of inhibiting at least one serine/threonine kinase in the MAPK signaling pathway in a subject, or treating a biological condition mediated by a serine/threonine kinase in the MAPK signaling pathway in a subject, comprising: administering to the subject a solid form of the invention or a pharmaceutical composition thereof.
  • the present invention further provides method of inhibiting a receptor tyrosine kinase in a subject or treating a biological condition mediated by the receptor tyrosine kinase in a subject, comprising administering to the subject a solid form of the invention, or a pharmaceutical composition thereof.
  • the present invention further provides a solid form herein for use in therapy, such as according to any one or more of the therapeutic methods described herein.
  • the present invention further provides a solid form here for use in the preparation of a medicament for use in therapy, such as according to any one or more of the therapeutic methods described herein.
  • FIG. 1 depicts an XRPD spectrum consistent with Form A.
  • FIG. 2 depicts an XRPD spectrum consistent with Form B.
  • FIG. 3 depicts an XRPD spectrum consistent with Form C.
  • FIG. 4 depicts an XRPD spectrum consistent with Form D.
  • FIG. 5 depicts an XRPD spectrum consistent with Form E.
  • FIG. 6 depicts an XRPD spectrum consistent with Form F.
  • FIG. 7 depicts an XRPD spectrum consistent with Form G.
  • FIG. 8 depicts an XRPD spectrum consistent with Form H.
  • FIG. 9 depicts an XRPD spectrum consistent with Form I.
  • FIG. 10 depicts an XRPD spectrum consistent with Form J.
  • FIG. 11 depicts an XRPD spectrum consistent with Form K.
  • FIG. 12 depicts an XRPD spectrum consistent with Form L.
  • FIG. 13 depicts an XRPD spectrum consistent with Form M.
  • FIG. 14 depicts an XRPD spectrum consistent with Form N.
  • FIG. 15 depicts an XRPD spectrum consistent with Form O.
  • FIG. 16 depicts an XRPD spectrum consistent with Form P.
  • FIG. 17 depicts a DSC thermogram consistent with Form A.
  • FIG. 18 depicts a DSC thermogram consistent with Form B.
  • FIG. 19 depicts a DSC thermogram consistent with Form C.
  • FIG. 20 depicts a DSC thermogram consistent with Form D.
  • FIG. 21 depicts a DSC thermogram consistent with Form E.
  • FIG. 22 depicts a DSC thermogram consistent with Form F.
  • FIG. 23 depicts a DSC thermogram consistent with Form G.
  • FIG. 24 depicts a DSC thermogram consistent with Form H.
  • FIG. 25 depicts a DSC thermogram consistent with Form I.
  • FIG. 26 depicts a DSC thermogram consistent with Form J.
  • FIG. 27 depicts a DSC thermogram consistent with Form K.
  • FIG. 28 depicts a DSC thermogram consistent with Form L.
  • FIG. 29 depicts a DSC thermogram consistent with Form M.
  • FIG. 30 depicts a DSC thermogram consistent with Form N.
  • FIG. 31 depicts a DSC thermogram consistent with Form O.
  • FIG. 32 depicts a DSC thermogram consistent with Form P.
  • FIG. 33 depicts a TGA thermogram consistent with Form A.
  • FIG. 34 depicts a TGA thermogram consistent with Form B.
  • FIG. 35 depicts a TGA thermogram consistent with Form C.
  • FIG. 36 depicts a TGA thermogram consistent with Form D.
  • FIG. 37 depicts a TGA thermogram consistent with Form E.
  • FIG. 38 depicts a TGA thermogram consistent with Form F.
  • FIG. 39 depicts a TGA thermogram consistent with Form G.
  • FIG. 40 depicts a TGA thermogram consistent with Form H.
  • FIG. 41 depicts a TGA thermogram consistent with Form I.
  • FIG. 42 depicts a TGA thermogram consistent with Form J.
  • FIG. 43 depicts a TGA thermogram consistent with Form K.
  • FIG. 44 depicts a TGA thermogram consistent with Form L.
  • FIG. 45 depicts a TGA thermogram consistent with Form M.
  • FIG. 46 depicts a TGA thermogram consistent with Form N.
  • FIG. 47 depicts a TGA thermogram consistent with Form O.
  • FIG. 48 depicts a TGA thermogram consistent with Form P.
  • the present invention provides, inter alia, solid forms (Forms A-P) of the Raf kinase inhibitor 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine (see Example 17 for a general preparation of this compound).
  • Each of the solid forms can be identified by one or more solid state analytical methods such as X-ray powder diffraction (XRPD), optionally in combination with thermal analysis by differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA).
  • solid form is meant to include any solid phase embodiment of the compound 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, including both amorphous and crystalline solid forms.
  • solid form is further meant to encompass both anhydrous and unsolvated solids as well as various hydrated and solvated forms.
  • XRPD collection parameters are provided in Example 18.
  • the relative intensities of the XRPD peaks can vary depending on, inter alia, the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Accordingly, the term “substantially” in the context of XRPD is meant to encompass that peak assignments can vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings used.
  • Solid forms are characterized as having “substantially no peak” over a designated 2-theta region.
  • substantially no peak is meant that there is no detectable peak in the designated region having an intensity of more than about 2% of the intensity of the strongest peak in the entire pattern.
  • the solid forms described herein are further characterized by DSC and TGA.
  • Parameters for thermal data collection are provided in Example 19.
  • the thermal value of DSC or TGA events can vary depending on, inter alia, the particle size distribution, the presence of impurities, the heating rate, and the type of instrument used. Accordingly, the temperature reading for DSC and TGA thermograms can vary about ⁇ 4° C., and thus a solid form having a DSC or TGA thermogram “substantially” as shown in a specified Figure is understood to accommodate such variation.
  • the solid forms can be prepared according to standard methods including, for example, precipitation from a solution containing 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • Precipitation can be induced by any of many routine methods including temperature reduction (cooling), solvent evaporation, addition of antisolvent (e.g., directly, by layer diffusion or vapor diffusion), or combinations of these techniques.
  • the solid forms can be made by slurrying solid 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine in organic or aqueous solvents.
  • solid forms of the same substance have different bulk properties relating to, for example, hygroscopicity, solubility, stability, and the like.
  • Forms with high melting points often have good thermodynamic stability which is advantageous in prolonging shelf-life drug formulations containing the solid form.
  • Forms with lower melting points often are less thermodynamically stable, but are advantageous in that they have increased water solubility, translating to increased drug bioavailability.
  • Forms that are weakly hygroscopic are desirable for their stability to heat and humidity and are resistant to degradation during long storage.
  • Anhydrous forms are often desirable because they can be consistently made without concern for variation in weight or composition due to varying solvent or water content.
  • hydrated or solvated forms can be advantageous in that they are less likely to be hygroscopic and may show improved stability to humidity under storage conditions.
  • Solid Form A of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine is a crystalline form characterized by an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 9.0°, about 17.0°, about 18.4°, and about 25.3°, wherein the pattern comprises no substantial peak at 2 ⁇ values below the peak at about 9.0°. In some embodiments, the pattern further comprises no substantial peak at 2 ⁇ values from about 14.5° to about 16.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 12.1°, about 14.1°, or about 18.7°. In some embodiments, pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 19.5°, about 21.8°, about 21.0°, about 22.7°, about 27.0°, or about 28.0°.
  • the solid form has an XRPD pattern substantially as shown in FIG. 1 (peaks are listed in Table A).
  • Form A is characterized by a DSC thermogram comprising endotherms at about 130 and about 170° C. In yet further embodiments, Form A is characterized by a DSC thermogram substantially as shown in FIG. 17 .
  • TGA data related to Form A evidenced a hydrate or solvate.
  • TGA revealed a 3-3.5% mass loss which is consistent with a monohydrate.
  • the present invention includes hydrates of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, including the monohydrate form.
  • Form A can be prepared by precipitation of the form from a solution comprising an organic solvent and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • Suitable organic solvents include any organic solvent that is miscible with water and in which 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine is at least slightly soluble.
  • Example organic solvents include nitriles (acetonitrile, propionitrile, etc.), alcohols (methanol, ethanol, etc.), acetic acid, ketones (acetone, methylethyl ketone, etc.), esters (ethyl acetate, etc.), halogenated hydrocarbons (methylene chloride, chlorobenzene, etc.), and mixtures thereof.
  • the precipitation is carried out in the presence of water.
  • the organic solvent can contain water or the precipitation can be carried out exposed to humid air.
  • Form A has numerous advantages that are readily apparent to the skilled artisan. For example, Form A can be obtained by precipitation from a variety of solvent conditions, indicating that it is a relatively stable form that would likely enjoy a relatively long shelf life. Additionally, because Form A is a hydrate, use of rigorously dry solvents, which can increase production costs, would not be required in the preparation, and exposure to humidity during storage would likely not be as much as a concern as for anhydrous or other forms.
  • Form B of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 8.7°, about 12.2°, about 13.6°, about 17.9° and about 24.5°, wherein the pattern comprises no substantial peak at 2 ⁇ values below the peak at about 8.7°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 16.3°, about 19.2°, or about 20.6°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 21.8°, about 26.0°, about 28.2°, or about 30.2°.
  • the solid form has an XRPD pattern substantially as shown in FIG. 2 (peaks are listed in Table B).
  • Form B is characterized by a DSC thermogram comprising an endotherm at about 210° C. In yet further embodiments, Form B is characterized by a DSC thermogram substantially as shown in FIG. 18 .
  • Form B can be prepared by any of numerous methods including precipitation of the solid form from a solution comprising an organic solvent and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • the organic solvent can include, for example, ketones (acetone, 2-butanone, methylethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, etc.) and mixtures thereof.
  • the organic solvent is substantially free of water.
  • Form B The numerous advantages of Form B are readily apparent to the art skilled. For example, anhydrous and unsolvated solids are advantageous in that can be reproducibly formed without concern for variation in weight or composition due to varying solvent/water content.
  • Form C is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 6.7°, about 7.6°, about 9.2°, about 9.6°, and about 15.3°, wherein the pattern comprises no substantial peak at 2 ⁇ values from about 9.8° to about 11.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 14.6°, about 17.6°, about 18.8°, about 19.4°, or about 20.2°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.8°, about 21.7°, about 23.5°, about 24.0°, about 26.1°, about 27.5°, about 29.1°, or about 30.5°.
  • the XRPD pattern is as substantially shown in FIG. 3 (peaks are listed in Table C).
  • Form C is characterized by a DSC thermogram comprising an endotherm at about 183° C. In yet further embodiments, Form C is characterized by a DSC thermogram substantially as shown in FIG. 19 .
  • Form C can be prepared by a plurality of methods including suspending 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine in an aliphatic hydrocarbon solvent (alkanes, alkenes, alkynes, etc.) or precipitating the solid form from a solution comprising an aliphatic hydrocarbon solvent (hexane, etc.) and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • an aliphatic hydrocarbon solvent alkanes, alkenes, alkynes, etc.
  • Form D is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 6.5° and about 11.6°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 7.5°, about 9.3°, about 14.8°, about 15.5°, about 17.4°. or about 18.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 18.8°, about 19.6°, about 20.3°, about 22.3°, about 23.5°, about 24.4°, about 25.4°, about 26.0°, or about 27.7°.
  • the XRPD pattern is as substantially shown in FIG. 4 (peaks are listed in Table D).
  • Form D is characterized by a DSC thermogram comprising an endotherm at about 184° C. In yet further embodiments, Form D is characterized by a DSC thermogram substantially as shown in FIG. 20 .
  • Form D can be prepared by any of the various methods comprising suspending 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine in an aromatic hydrocarbon solvent (toluene, etc.) or precipitating the solid form from a solution comprising an aromatic hydrocarbon solvent (toluene, etc.) and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • Form E is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 7.5° and about 10.6°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 6.8°, about 9.8°, about 10.6°, or about 16.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 17.4°, about 18.6°, about 19.3°, about 22.5°, about 23.5°, about 24.8°, or about 25.8°.
  • Form E has an XRPD pattern substantially as shown in FIG. 5 (peaks are listed in Table E).
  • Form E is characterized by a DSC thermogram comprising endotherms at about 179 and about 186° C. In yet further embodiments, Form E is characterized by a DSC thermogram substantially as shown in FIG. 21 .
  • Form E can be prepared by various methods. For example, 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine can be dissolved in an alcohol, such as ethanol, optionally under reflux, to achieve a homogeneous solution. Then the alcohol can be removed by, for example, distillation resulting in a slurry that can be treated with water and cooled. The solid product can be isolated, washed, and dried under vacuum until constant weight.
  • an alcohol such as ethanol
  • the alcohol can be removed by, for example, distillation resulting in a slurry that can be treated with water and cooled.
  • the solid product can be isolated, washed, and dried under vacuum until constant weight.
  • Form F of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 20, at about 5.8° and about 19.6°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 15.8°, about 16.8°, about 17.5°, about 18.2°, or about 18.8°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.3°, about 21.7°, about 22.7°, about 23.0°, about 24.3°, about 25.7°, about 27.9°, or about 29.5°.
  • the XRPD pattern is as substantially shown in FIG. 6 (peaks are listed in Table F).
  • Form F is characterized by a DSC thermogram substantially as shown in FIG. 22 .
  • Form F can be prepared by numerous methods comprising heating 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine to a temperature of about 200 to 230° C. followed by cooling or suspending the product of the above process in an organic solvent followed by cooling and precipitation.
  • the organic solvent can comprise ethyl acetate or other organic ester.
  • Form G of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine is characterized as an amorphous or a nanocrystalline form having an X-ray powder diffraction pattern substantially as shown in FIG. 7 (peaks are listed in Table G).
  • Form G is characterized by a DSC thermogram comprising an endotherm at about 228° C.
  • Form G is characterized by a DSC thermogram substantially as shown in FIG. 23 .
  • Form G is characterized by a TGA thermogram substantially as shown in FIG. 39 .
  • Form G can be prepared via a process comprising precipitating the solid form from a solution comprising an organic solvent such as an ether (e.g. tetrahydrofuran) and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • an organic solvent such as an ether (e.g. tetrahydrofuran) and 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • Form H is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 9.6°, about 13.8°, and about 12.2°, wherein the pattern comprises no substantial peak at 2 ⁇ values less than about 9.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 11.5°, about 11.8°, about 15.8°, about 16.7°, or about 19.2°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.7°, about 21.8°, about 22.2°, about 22.6°, about 24.3°, about 24.9°, about 25.6°, about 28.0°, about 29.9°, about 32.9°, or about 35.1°.
  • the solid form (Form H) has a powder X-ray diffraction pattern substantially as shown in FIG. 8 (peaks are listed in Table H).
  • the solid form is characterized by a DSC thermogram comprising an endotherm at about 159° C. In yet further embodiments, the form is characterized by a DSC thermogram substantially as shown in FIG. 24 .
  • TGA data of Form H evidenced a hydrate or solvate.
  • TGA ( FIG. 40 ) revealed a 6-8% mass loss which is consistent with an ethanol solvate consisting of about one mole of ethanol per one mole of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.
  • Form H can be prepared by cooling or evaporating a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine and alcohol such as ethanol.
  • Form I is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 11.1° and about 32.4°, wherein the pattern comprises no substantial peak at 2 ⁇ values of about 12.5° to about 14.5°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 12.1°, about 15.3°, about 17.1°, about 18.9°, or about 19.5°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.5°, about 21.9°, about 22.1°, about 24.3°, about 26.3°, or about 27.9°.
  • Form I is characterized by an XRPD pattern substantially as shown in FIG. 9 (peaks are listed in Table I).
  • Form I is characterized by a DSC thermogram comprising an endotherm at about 232° C. In yet further embodiments, Form I exhibits a DSC thermogram substantially as shown in FIG. 25 .
  • Form I can be prepared by precipitating the solid form from a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine and dioxane. Precipitation can comprise cooling and evaporation crystallization of the solid form from dioxane solution.
  • Form J is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 7.1°, about 14.2°, and about 29.5°, wherein the pattern comprises no substantial peak at 2 ⁇ values of about 11.0° to about 12.5°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 10.5°, about 12.9°, about 17.8°, about 18.7°, or about 20.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.9°, about 23.4°, about 23.9°, about 25.2°, about 26.3°, about 31.7°, about 33.3°, or about 36.0°.
  • Form J is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 10 (peaks are listed in Table J).
  • Form J is further characterized by a DSC thermogram comprising an endotherm at about 195 to about 205° C.
  • the solid form has a DSC thermogram substantially as shown in FIG. 26 .
  • Form J is a hydrate or solvate.
  • Form J is an N-methylpyrrolidinone solvate.
  • Form J can be prepared by precipitation of the solid form from a solution of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine in N-methylpyrrolidinone or in dimethylacetamide.
  • Form K is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 6.4°, about 10.6°, and about 19.7°, wherein the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 12.7°, about 14.5°, about 15.2°, or about 17.4°. In some embodiments, the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 21.3°, about 24.7°, about 28.6°, or about 29.6°. In further embodiments, the solid form exhibits a powder X-ray diffraction pattern substantially as shown in FIG. 11 (peaks are listed in Table K).
  • Form K is further characterized by a DSC thermogram comprising an endotherm at about 192° C. In yet further embodiments, Form K is characterized by a DSC thermogram substantially as shown in FIG. 27 .
  • TGA and DSC data suggest that Form K is an anhydrate or is unsolvated. See FIG. 43 for TGA data characterizing Form K.
  • Form K can be prepared by precipitating the solid form from a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine and methanol.
  • Form L is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 9.1°, about 10.1°, about 11.1°, and about 12.0°, wherein the pattern comprises no substantial peak at 2 ⁇ values below about 8.5°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 14.9°, about 16.1°, about 17.2°, about 18.3°, or about 19.0°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 20.3°, about 21.2°, about 22.2°, about 23.3°, about 24.0°, about 25.8°, about 27.5°, about 28.1°, or about 30.2°.
  • the solid form is characterized by an XRPD pattern substantially as shown in FIG. 12 (peaks are listed in Table L).
  • Form L is further characterized by a DSC thermogram comprising an endotherm at about 212° C.
  • the solid form is characterized by a DSC thermogram substantially as shown in FIG. 28 .
  • Form L can be prepared by precipitating the solid form from a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, a trialkylamine, and tetrahydrofuran.
  • Form M is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 10.4°, about 14.7°, and about 16.4°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 12.2°, about 17.2°, about 19.1°, or about 19.4°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 19.9°, about 21.3°, about 22.8°, about 24.2°, about 24.7°, about 25.6°, or about 26.9°.
  • the solid form has a powder X-ray diffraction pattern substantially as shown in FIG. 13 (peaks are listed in Table M).
  • Form M is further characterized by a DSC thermogram comprising an endotherm at about 214° C.
  • the solid form has a DSC thermogram substantially as shown in FIG. 29 .
  • Form M can be prepared by precipitating the solid form from a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, a trialkylamine, and ethyl acetate or other organic ester.
  • Form N of 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 10.0°, about 15.3°, about 16.1°, and about 20.1°, wherein the pattern comprises no substantial peak at 2 ⁇ values below about 7.0°, wherein the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 14.5°, about 16.7°, about 18.0°, about 18.9°, about 19.1°, or about 20.7°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 21.1°, about 23.4°, about 24.5°, about 25.4°, about 27.0°, about 28.3°, or about 29.8°.
  • Form N has a powder X-ray diffraction pattern substantially as shown in FIG. 14 (peaks are listed in Table N).
  • Form N is characterized by a DSC thermogram comprising an endotherm at about 220° C. In yet further embodiments, Form N has a DSC thermogram substantially as shown in FIG. 30 .
  • Form N is suggested as a hydrate or solvate by TGA and DSC analysis. See FIG. 46 for TGA data characterizing the solid form.
  • Form N can be prepared by suspending 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine in a glycol such as propylene glycol.
  • Form O is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 12.6°, about 17.2°, about 25.3°, and about 33.1°, wherein the pattern comprises no substantial peak at 2 ⁇ values of about 23.0° to about 24.5°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 18.5°, about 20.9°, about 22.8°, about 28.0°, or about 30.3°.
  • Form O has an XRPD pattern substantially as shown in FIG. 15 (peaks are listed in Table O).
  • the solid form is characterized by a DSC thermogram comprising an endotherm at about 190° C.
  • Form O is characterized by a DSC thermogram substantially as shown in FIG. 31 .
  • TGA and DSC analysis suggest that Form O is a hydrate or solvate. See FIG. 47 for TGA data characterizing the solid form.
  • Form O can be prepared by precipitating the solid form from a solution comprising 1-methyl-5-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine and methanol.
  • Form P is characterized as a crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2 ⁇ , at about 7.2° and about 10.2°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 8.4°, about 13.7°, about 17.0°, or about 19.6°.
  • the pattern further comprises at least one characteristic peak, in terms of 2 ⁇ , at about 21.4°, about 22.7°, about 23.3°, about 23.7°, about 25.4°, about 28.1°, or about 31.2°.
  • Form P has an XRPD pattern substantially as shown in FIG. 16 (peaks are listed in Table P).
  • Form P is characterized by a DSC thermogram comprising an endotherm at about 212° C. In yet further embodiments, Form P exhibits a DSC thermogram substantially as shown in FIG. 32 .
  • Form P can be prepared by precipitation of the solid from a solution comprising 1-methyl-5-(2-(5-trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine, trialkylamine, and an ether such as tetrahydrofuran.
  • the present invention provides methods for inhibiting the enzyme Raf kinase. Since the enzyme is a downstream effector of p21 ras , the instant solid forms are useful alone or in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by Raf kinase. In particular, the solid forms are useful in the treatment of human or animal (e.g., murine) cancer, since the progression of these cancers can often be dependent upon the Ras protein signal transduction cascade and therefore is susceptible to treatment by interruption of the cascade by inhibiting Raf kinase activity.
  • human or animal e.g., murine
  • the solid forms of the invention are useful in treating a variety of cancers, including solid cancers such as for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia, multiple myeloma, and erythroleukemia), adenomas (e.g., villous colon adenoma), sarcomas (e.g., osteosarcoma), and the like.
  • carcinomas e.g., of the lungs, pancreas, thyroid, bladder or colon
  • myeloid disorders e.g., myeloid leukemia, multiple myeloma, and erythroleukemia
  • adenomas e.g., villous colon adenoma
  • sarcomas e.g., osteosarcoma
  • cancer refers to cancer diseases that can be beneficially treated by the inhibition of a kinase, particularly Raf kinase, including, for example, solid cancers, such as those described above including carcinomas (e.g., of the lungs, pancreas, thyroid, ovarian, bladder, breast, prostate, or colon), melanomas, myeloid disorders (e.g., myeloid leukemia, multiple myeloma, and erythroleukemia), adenomas (e.g., villous colon adenoma), and sarcomas (e.g., osteosarcoma).
  • carcinomas e.g., of the lungs, pancreas, thyroid, ovarian, bladder, breast, prostate, or colon
  • melanomas e.g., myeloid disorders (e.g., myeloid leukemia, multiple myeloma, and erythroleukemia), adenomas (e.g., villous colon
  • Raf inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to Raf Kinase activity of no more than about 100 ⁇ M and more typically not more than about 50 ⁇ M, as measured in the Raf/Mek Filtration Assay described generally hereinbelow in the Examples.
  • Preferred isoforms of Raf kinase in which the solid forms of the present invention can inhibit include A-Raf, B-Raf, and C-Raf (Raf-1).
  • IC 50 is that concentration of inhibitor which reduces the activity of an enzyme (e.g., Raf kinase) to half-maximal level.
  • Methods of treating the diseases listed herein are understood to involve administering to a human or animal in need of such treatment an effective amount of the solid form of the invention, or composition containing the same.
  • treating in reference to a disease is meant to refer to preventing, inhibiting and/or ameliorating the disease.
  • effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amounts of the solid forms of the invention generally include any amount sufficient to detectably inhibit Raf activity by any of the assays described herein, by other Raf kinase activity assays known to or readily ascertained by those having ordinary skill in the art or by detecting an inhibition or alleviation of symptoms of cancer.
  • the present invention relates to methods of inhibiting at least one serine/threonine kinase in the MAPK signaling pathway in a subject, or treating a biological condition mediated by a serine/threonine kinase in the MAPK signaling pathway in a subject, comprising administering a solid form of the invention in an amount effective to inhibit the activity of the at least one serine/threonine kinase in the MAPK signaling pathway in the subject.
  • MAPK signal transduction pathway is an abbreviation that stands for Mitogen activated protein kinase signal transduction pathway in a module that is formed of the Ras-Raf-MEK1-ERK signaling molecules.
  • the therapeutic compositions in accordance with this aspect of the invention are useful for treating patients with a need for such inhibitors (e.g., those suffering from cancer mediated by abnormal MAPK signaling).
  • Cancer types mediated by abnormal MAPK signaling include, for example, melanoma, papillary thyroid cancer, thyroid cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), leukemia (acute lymphoblastic leukemia (ALL) and acute myeloid leukemia) and the like.
  • Abnormal MAPK signaling may be inhibited by administering a compound that inhibits wild-type or mutant forms of Ras, Raf, MEK or ERK.
  • the invention provides a method of inhibiting Ras (wild-type or mutant Ras).
  • the method includes administering an effective amount of any of the solid forms described herein to a subject in need thereof.
  • the invention provides a method of inhibiting Raf (wild-type, or mutant B-Raf).
  • the method includes administering an effective amount of any of the solid forms described herein to a subject in need thereof.
  • the invention provides a method of inhibiting MEK.
  • the method includes administering an effective amount of any of the solid forms described herein to a subject in need thereof.
  • the invention provides a method of inhibiting ERK.
  • the method includes administering an effective amount of any of the solid forms described herein to a subject in need thereof.
  • the present invention relates to methods of inhibiting at least one tyrosine kinase receptor selected from the group consisting of VEGFR-2, PDGFR- ⁇ , pERK, bFGF, FGFR1, FGFR2, FGFR3, c-Kit and CSF-1R in a subject, or treating a biological condition mediated by at least one of VEGFR-2, PDGFR- ⁇ , pERK, bFGF, FGFR1, FGFR2, FGFR3, c-Kit and CSF-1R, comprising administering a therapeutic composition comprising at least one solid form of the invention in an amount effective to inhibit the tyrosine kinase receptor in the subject.
  • the therapeutic solid forms in accordance with this aspect of the invention are useful for treating patients with a need for such inhibitors (e.g., those suffering from cancer mediated by abnormal tyrosine kinase receptor signaling).
  • Cancers mediated by abnormal tyrosine kinase receptor signaling include, for example, melanoma, breast cancer, bladder cancer, lung cancer, thyroid cancer, prostate cancer, ovarian cancer, mast cell leukemia, germ cell tumors, small-cell lung carcinoma, gastrointestinal stromal tumors, acute myelogenous leukemia (AML), neuroblastoma, and pancreatic cancer.
  • cancers mediated by abnormal tyrosine kinase receptor include leukemia, erythroleukemia, germ cell tumors, small-cell lung carcinoma, gastrointestinal stromal tumors, acute myelogenous leukemia, neuroblastoma, melanoma, multiple myeloma, ovarian carcinoma, and breast carcinoma.
  • the invention provides a method of inhibiting VEGFR-2.
  • the method includes administering an effective amount of a solid form of the invention to a subject in need thereof.
  • the method may be useful to treat a solid tumor by inhibiting angiogenesis.
  • the invention provides a method of inhibiting PDGFR- ⁇ .
  • the method includes administering an effective amount of a solid form of the invention to a subject in need thereof.
  • the invention provides a method of inhibiting c-Kit.
  • the method includes administering an effective amount of a solid form of the invention to a subject in need thereof.
  • the invention provides a method of inhibiting CSF-1R.
  • the method includes administering an effective amount of a solid form of the invention to a subject in need thereof.
  • the solid forms of the invention are useful in vitro or in vivo in inhibiting the growth of cancer cells.
  • the compounds may be used alone or in compositions together with one or more pharmaceutically acceptable carriers or excipients.
  • suitable pharmaceutically acceptable carriers or excipients include, for example, processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof.
  • Other suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • a therapeutically effective dose will generally be a total daily dose administered to a host in single or divided doses may be in amounts, for example, of from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the solid forms of the present invention may be administered orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • the solid forms of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology , Volume XIV, Academic Press, New York, N.W., p. 33 et seq. (1976).
  • solid forms of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of cancer.
  • the compounds of the present invention are also useful in combination with known therapeutic agents and anti-cancer agents, and combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology , V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, and agents that interfere with cell cycle checkpoints.
  • the solid forms of the invention are also useful when co-administered with radiation therapy.
  • the compounds of the invention are also used in combination with known anticancer agents including, for example, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • known anticancer agents including, for example, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors.
  • Estrogen receptor modulators are compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Androgen receptor modulators are compounds which interfere with or inhibit the binding of androgens to an androgen receptor.
  • Representative examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators are compounds which interfere or inhibit the binding of retinoids to a retinoid receptor.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, LX23-7553, trans-N-(4′-hydroxyphenyl) retinamide, and N4-carboxyphenyl retinamide.
  • Cytotoxic and/or cytostatic agents are compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds; microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors, and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-m
  • Proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.
  • microtubule inhibitors/microtubule-stabilizing agents include paclitaxel, vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L
  • topoisomerase inhibitors include topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BN
  • inhibitors of mitotic kinesins such as the human mitotic kinesin KSP
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1, and inhibitors of Rab6-KIFL.
  • Inhibitors of kinases involved in mitotic progression include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (e.g., inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1.
  • PLK Polo-like kinases
  • Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea
  • Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include, for example, Bexxar.
  • HMG-CoA reductase inhibitors are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art such as those described or cited in U.S. Pat. No. 4,231,938 and WO 84/02131.
  • HMG-CoA reductase inhibitors examples include, but are not limited to, lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926, and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850, and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447, and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos.
  • HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.
  • Prenyl-protein transferase inhibitors are compounds which inhibit any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibiting compounds include ( ⁇ )-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone, ( ⁇ )-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, 5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl-2-piperazinone,
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-.alpha., interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS 89:7384 (1992); JNCI 69:475 (1982); Arch.
  • NSAIDs non
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone
  • carboxyamidotriazole combretastatin A4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med.
  • VEGF vascular endothelial growth factor
  • Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost.
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).
  • the invention also encompasses combinations of the compounds of the invention with NSAIDs which are selective COX-2 inhibitors (generally defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC 50 for COX-2 over IC 50 for COX-1 evaluated by cell or microsomal assays).
  • NSAIDs selective COX-2 inhibitors
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr.
  • Representative inhibitors of COX-2 that are useful in the methods of the present invention include 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrol
  • Agents that interfere with cell cycle checkpoints are compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA.damaging agents.
  • Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • Inhibitors of cell proliferation and survival signaling pathway are pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK (for example CI-1040 and PD-098059) and inhibitors of mTOR (for example Wyeth CCI-779).
  • Such agents include small molecule inhibitor compounds and antibody antagonists.
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • representative agents useful in combination with the solid forms of the invention for the treatment of cancer include, for example, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines, rituximab, trastuzumab, as well as other cancer chemotherapeutic agents.
  • the solid forms of the invention and the other anticancer agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
  • the combination can be administered as separate compositions or as a single dosage form containing both agents.
  • the therapeutic agents can be formulated as separate compositions, which are given at the same time or different times, or the therapeutic agents, can be given as a single composition.
  • Antiestrogens such as tamoxifen, inhibit breast cancer growth through induction of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip.
  • activation of the Ras-Raf-MAP Kinase pathway alters the phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell cycle is attenuated, thereby contributing to antiestrogen resistance (Donovan et al., J. Biol. Chem. 276:40888, 2001).
  • inhibition of MAPK signaling through treatment with MEK inhibitor changed the phosphorylation status of p27 in hormone refactory breast cancer cell lines and in so doing restored hormone sensitivity.
  • any of the solid forms described herein may be used in the treatment of hormone dependent cancers, such as breast and prostate cancers, to reverse hormone resistance commonly seen in these cancers with conventional anticancer agents.
  • chromosomal translocation is responsible for the constitutively activated BCR-AB1 tyrosine kinase.
  • CML chronic myelogenous leukemia
  • the afflicted patients are responsive to Gleevec, a small molecule tyrosine kinase inhibitor, as a result of inhibition of Ab1 kinase activity.
  • Gleevec a small molecule tyrosine kinase inhibitor
  • BCR-Av1 employs the Raf kinase pathway to elicit its effects.
  • any of the solid forms described herein can be used in combination with at least one additional agent, such as Gleevec, in the treatment of hematological cancers, such as chronic myelogenous leukemia (CML), to reverse or prevent resistance to the at least one additional agent.
  • at least one additional agent such as Gleevec
  • the crystalline product was analyzed by XRPD, DSC, and TGA (See FIGS. 5 , 21 , and 37 ).
  • the filtrate from above was allowed to air-dry for 4 days.
  • the crystalline product was analyzed by XRPD, DSC, and TGA (See FIGS. 9 , 25 , and 41 ) and was found consistent with Form I.
  • Example 11 The filtrate from Example 11 was allowed to air-dry for 4 days.
  • the product was analyzed by XRPD, DSC, and TGA (See FIGS. 15 , 31 , and 47 ).
  • Example 12 The filtrate from Example 12 was allowed to air-dry for 4 days.
  • the product was analyzed by XRPD, DSC, and TGA (See FIGS. 16 , 32 , and 48 ).
  • a 500 mL three-neck flask was fitted with a mechanical stirrer and charged with K 2 CO 3 (4.15 g, 30 mmol). The vessel was sealed, evacuated, and flame dried. The apparatus was allowed to cool to rt and purged with argon. To the reaction flask was added 4-amino-3-nitrophenol 1a (3.08 g, 20 mmol), tert-butyl 4-chloropyridine-2-carboxylate 1b (5.2 g, 24 mmol) and dry dimethylsulfoxide (DMSO) (30 mL). The resulting mixture was stirred vigorously and heated to 100° C. for ⁇ 14 h.
  • DMSO dry dimethylsulfoxide
  • MTBE methyl t-butyl ether
  • the combined biphasic mixture was filtered through Celite (>2 cm pad).
  • the layers were partitioned and separated and the aqueous phase was extracted with MTBE (3 ⁇ 100 mL).
  • the combined organic layers were washed with water (5 ⁇ 100 mL), dried (MgSO 4 ), and evaporated.
  • the crude residue was adsorbed onto SiO 2 , and purified by flash chromatography (4:1, 2:1, 1:1 hexanes/EtOAc) to furnish 4.92 g (14.9 mmol, 74% yield) of 1c as a yellow brown solid.
  • the aqueous phase was extracted with CH 2 Cl 2 (3 ⁇ 100 mL), and the combined organic layers were washed with brine (2 ⁇ 100 mL), dried (MgSO 4 ), and evaporated.
  • the crude residue was adsorbed onto silica gel and purified by flash chromatography (4:1, 2:1, 1:1, 1:2 hexanes/EtOAc) to give 4.5 g (13.0 mmol, 76%) of 1d as a yellow-orange solid.
  • Ketone 1g (Lancaster, 25.75 mL, 136.5 mmol) was added to a solution of sodium acetate (NaOAc) (22.4 g, 273 mmol) in H 2 O (60 mL) and the resulting solution heated to 100° C. for 10 min. After cooling to rt, the solution of 1h was added to a suspension of 1f (25 g, 91 mmol) in NH 4 OH (150 mL) and MeOH (450 mL). The resulting mixture was stirred at rt overnight. TLC (95:5 CH 2 Cl 2 /MeOH) showed complete consumption of 1f.
  • the crude product was concentrated into an aqueous slurry, and partitioned with saturated Na 2 CO 3 and CH 2 Cl 2 .
  • the aqueous phase was extracted three times with CH 2 Cl 2 , and the combined organics washed with brine, dried with MgSO 4 , and concentrated to give 31.6 g of 1i (83 mmol) as an orange solid (91% yield). No further purification was required.
  • the layers were separated, and the aqueous phase was extracted with EtOAc (aqueous phase saved).
  • the organic layers were combined, washed with saturated aqueous Na 2 CO 3 solution, water, and brine, then dried (MgSO 4 ), and concentrated.
  • 1,1-Dibromo-3,3,3-trifluoroacetone was added to an aqueous sodium acetate solution. The mixture was heated until it was complete by GC. The reaction mixture, containing was then cooled and added to an ethanol/ethyl acetate solution of 4-(4-methylamino-3-nitrophenol)pyridine-2-carbaldehyde. After the addition was complete, ammonium hydroxide was added and the reaction mixture heated until the reaction was complete by HPLC. The reaction mixture was cooled and the product filtered and washed with water. The yellow solid (3) was then dried under vacuum until a constant weight is obtained.
  • the product was dissolved in a sufficient amount of refluxing ethanol to achieve a homogeneous solution.
  • the title compound was crystallized out of solution by removal of ethanol by distillation. After distillation of ethanol, the resultant slurry was treated with water and the solution cooled. The solid product was was filtered, washed with ethanol/water and dried under vacuum until constant weight to give the product title compound as an off-white to yellow/brown solid.
  • the XRPD analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu K ⁇ radiation.
  • the instrument was equipped with a long fine focus X-ray tube.
  • the tube voltage and amperage were set to 40 kV and 40 mA, respectively.
  • the divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm.
  • Diffracted radiation was detected by a NaI scintillation detector.
  • a ⁇ -2 ⁇ continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5 to 40° 2 ⁇ was used.
  • a silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1.
  • Raf and Mek are combined at 2 ⁇ final concentrations in assay buffer (50 mM Tris, pH 7.5, 15 mM MgCl 2 . 0.1 mM EDTA and 1 mM DTT) and dispensed 15 ⁇ L per well in polypropylene assay plates (Falcon U-bottom polypropylene 96 well assay plates #35-1190. Background levels are determined in wells containing Mek and DMSO without Raf.
  • raf kinase activity reaction is started by the addition of 12 ⁇ L per well of 2.5 ⁇ 33 P-ATP diluted in assay buffer. After 45-60 minutes, the reactions are stopped with the addition of 70 ⁇ L of stop reagent (30 mM EDTA). Filtration plates are pre-wetted for 5 min with 70% ethanol, and then rinsed by filtration with wash buffer. Samples (90 ⁇ L) from the reaction wells are then transferred to the filtration plates. The filtration plates are washed 6 ⁇ with wash buffer using Millipore filtration apparatus.
  • the plates are dried and 100 ⁇ L per well of scintillation fluid (Wallac OptiPhase “SuperMix” #1200-439) is added.
  • the CPM is then determined using a Wallac Microbeta 1450 reader.

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